DESCRIPTION (Taken from the applicant's abstract) Thyroid hormone plays a critical role in promoting normal growth and development and contributes to the normal functioning of numerous organ systems. Levels of thyroid hormone are tightly regulated via a feedback loop involving thyroid stimulating hormone (TSH) from the pituitary and thyrotropin releasing hormone (TRH) from the hypothalamus; increasing levels of thyroid hormone will inhibit the production and release of these neuroendocrine trophic hormones. Thyroid hormone mediates its effects via thyroid hormone receptors (TRs), which are ligand-dependent transcription factors. Much has been learned about the molecular mechanisms governing thyroid hormone action in peripheral tissues. Less is known about the ability of thyroid hormone to negatively regulate the secretion of TSH and TRH. Most of the previous work in the field has been performed using in vitro assays and cultured cell lines. Although valuable, a fuller understanding of the complex interactions of TR isoforms, accessory cofactors and target genes in determining the physiologic effects of thyroid hormone warrants the development of in vivo models. This project seeks to elucidate the molecular basis of thyroid hormone action in the pituitary in vivo by generating mouse models with discreet perturbations in the thyroid hormone action pathway. The studies proposed seek to determine the role of the respective isoforms of the TR by pituitary expression of isoform specific dominant negative mutations of the TR in transgenic mice, and by disrupting the pituitary specific TR isoform using gene targeting in embryonic stem cells. The study also seeks to determine the role of certain thyroid receptor related accessory proteins in vivo by inhibiting their function. Finally the molecular basis for pituitary resistance to thyroid hormone will be assessed by expressing one such mutant receptor in peripheral tissues in order to determine potential mechanisms for this disorder. This project will be performed by Dr. Evan Dale Abel under the guidance of Dr. Frederic Wondisford in the Thyroid Unit and Endocrine Division of the Beth Israel Hospital. Dr. Wondisford has made major contributions to the understanding of the molecular mechanisms governing negative regulation of the TSH and TRH genes. The Endocrine Division possesses state of the art transgenic and molecular biology facilities. In addition there are many investigators with similar or allied interests with whom the candidate will interact. Successful completion of this project in an environment committed to the training of young investigators should provide the basis for Dr. Abel's transition to independent research. The insight gained from these studies will significantly advance our understanding of the regulation of thyroid homeostasis by the pituitary.